Obesity, insulin resistance, and diabetes mellitus are the leading causes of renal and cardiovascular disease in the Veteran as well as in the general US population. In spite of all the beneficial interventions implemented, renal injury progresses in most of these patients. Additional treatment modalities that modulate the pathogenic pathways involved in obesity and diabetic nephropathy are therefore urgently needed. In this proposal we will test the potential role of inhibition of the sterol regulatory element binding proteins in prevention and treatment of kidney disease in obesity and diabetes. IN SPECIFIC AIM 1 WE WILL DETERMINE THE EFFECTS OF RENAL PODOCYTE SPECIFIC SREBP OVEREXPRESSION or RENAL PODOCYTE SPECIFIC SREBP DELETION IN KIDNEY DISEASE IN OBESITY AND DIABETES. In Specific Aim 1A we will determine the effects of diet induced obesity and diabetes in development of renal disease in a) wild type vs. b) podocyte SREBP overexpressing mice. In Specific Aim 1B we will determine the effects of diet induced obesity and diabetes in development of renal disease in a) wild type vs. b) podocyte SREBP knockout mice. In Specific Aim 1C we will determine the direct effects of SREBP silencing or overexpression in response of human podocytes to high glucose or fatty acids. IN SPECIFIC AIM 2 WE WILL DETERMINE THE EFFECTS OF SREBP ACTIVITY INHIBITION IN KIDNEY DISEASE IN OBESITY AND DIABETES. We will determine the effects of dissimilar inhibitors of SREBP activity 1) Betulin, 2) FGH10019, and 3) Metformin in diabetic kidney disease. In Specific Aim 2A we will perform preventive studies; that is treatments will be started at the onset of diabetes. In Specific Aim 2B we will perform treatment studies; that is treatments will be started once there is evidence of kidney disease which will better simulate the clinical setting. In Specific Aim 2C we will determine if Betulin, FGH10019, and Metformin have direct effects to modulate the response of human podocytes to high glucose and fatty acids and if these affects are specifically mediated via inhibition of SREBPs. Impact and Innovation: The potential role of the small molecule inhibitors of SREBP activation in modulating renal disease in obesity and diabetes renal disease is very novel and will have major translational implications for the treatment of diabetes and obesity-related renal and cardiovascular complications. Innovative aspects of this proposal include: a) Determine the effects of recently developed small molecule inhibitors of SREBP activity in the kidney; b) Study mice with kidney podocyte specific knockout or overexpression of SREBPs to determine the direct renal effects of SREBPs in regulation of renal lipid metabolism and kidney disease in obesity and diabetes. c) Determine the effects of SREBP overexpression or knockout and the small molecule inhibitors of SREBP activation in human podocyte cells in culture to determine the direct effects of SREBPs in renal cells independent of systemic alterations in metabolism; d) Mechanistic studies in podocytes in culture to determine how SREBPs modulate podocyte cell function and cell injury.